Community-based antiretroviral therapy versus standard clinic-based services for HIV in South Africa and Uganda (DO ART): a randomised trial

Background: Community-based delivery of antiretroviral therapy (ART) for HIV, including ART initiation, clinical and laboratory monitoring, and refills, could reduce barriers to treatment and improve viral suppression, reducing the gap in access to care for individuals who have detectable HIV viral load, including men who are less likely than women to be virally suppressed. We aimed to test the effect of community-based ART delivery on viral suppression among people living with HIV not on ART. / Methods: We did a household-randomised, unblinded trial (DO ART) of delivery of ART in the community compared with the clinic in rural and peri-urban settings in KwaZulu-Natal, South Africa and the Sheema District, Uganda. After community-based HIV testing, people living with HIV were randomly assigned (1:1:1) with mobile phone software to community-based ART initiation with quarterly monitoring and ART refills through mobile vans; ART initiation at the clinic followed by mobile van monitoring and refills (hybrid approach); or standard clinic ART initiation and refills. The primary outcome was HIV viral suppression at 12 months. If the difference in viral suppression was not superior between study groups, an a-priori test for non-inferiority was done to test for a relative risk (RR) of more than 0·95. The cost per person virally suppressed was a co-primary outcome of the study. This study is registered with ClinicalTrials.gov, NCT02929992. / Findings: Between May 26, 2016, and March 28, 2019, of 2479 assessed for eligibility, 1315 people living with HIV and not on ART with detectable viral load at baseline were randomly assigned; 666 (51%) were men. Retention at the month 12 visit was 95% (n=1253). At 12 months, community-based ART increased viral suppression compared with the clinic group (306 [74%] vs 269 [63%], RR 1·18, 95% CI 1·07–1·29; psuperiority=0·0005) and the hybrid approach was non-inferior (282 [68%] vs 269 [63%], RR 1·08, 0·98–1·19; pnon-inferiority=0·0049). Community-based ART increased viral suppression among men (73%, RR 1·34, 95% CI 1·16–1·55; psuperiority<0·0001) as did the hybrid approach (66%, RR 1·19, 1·02–1·40; psuperiority=0·026), compared with clinic-based ART (54%). Viral suppression was similar for men (n=156 [73%]) and women (n=150 [75%]) in the community-based ART group. With efficient scale-up, community-based ART could cost US$275–452 per person reaching viral suppression. Community-based ART was considered safe, with few adverse events. / Interpretation: In high and medium HIV prevalence settings in South Africa and Uganda, community-based delivery of ART significantly increased viral suppression compared with clinic-based ART, particularly among men, eliminating disparities in viral suppression by gender. Community-based ART should be implemented and evaluated in different contexts for people with detectable viral load. / Funding: The Bill & Melinda Gates Foundation; the University of Washington and Fred Hutch Center for AIDS Research; the Wellcome Trust; the University of Washington Royalty Research Fund; and the University of Washington King K Holmes Endowed Professorship in STDs and AIDS

Racism as a determinant of health: a systematic review and meta-analysis

Despite a growing body of epidemiological evidence in recent years documenting the health impacts of racism, the cumulative evidence base has yet to be synthesized in a comprehensive meta-analysis focused specifically on racism as a determinant of health. This meta-analysis reviewed the literature focusing on the relationship between reported racism and mental and physical health outcomes. Data from 293 studies reported in 333 articles published between 1983 and 2013, and conducted predominately in the U.S., were analysed using random effects models and mean weighted effect sizes. Racism was associated with poorer mental health (negative mental health: r = -.23, 95% CI [-.24,-.21], k = 227; positive mental health: r = -.13, 95% CI [-.16,-.10], k = 113), including depression, anxiety, psychological stress and various other outcomes. Racism was also associated with poorer general health (r = -.13 (95% CI [-.18,-.09], k = 30), and poorer physical health (r = -.09, 95% CI [-.12,-.06], k = 50). Moderation effects were found for some outcomes with regard to study and exposure characteristics. Effect sizes of racism on mental health were stronger in cross-sectional compared with longitudinal data and in non-representative samples compared with representative samples. Age, sex, birthplace and education level did not moderate the effects of racism on health. Ethnicity significantly moderated the effect of racism on negative mental health and physical health: the association between racism and negative mental health was significantly stronger for Asian American and Latino(a) American participants compared with African American participants, and the association between racism and physical health was significantly stronger for Latino(a) American participants compared with African American participants.<br /

Peptide Synthesis Using Proteases as Catalyst

Proteolytic enzymes (proteases) comprise a group of hydrolases (EC 3.4, NC-IUBMB) which share the common feature of acting on peptide bonds. Proteases are among the best studied enzymes in terms of structure-function relationship (Krowarsch et al., 2005). Proteases, by catalyzing the cleavage of other proteins and even themselves, have an enormous physiological significance, their coding genes representing as much as 2% of the total human genome (Schilling and Overall, 2008).Proteases, together with lipases, represent the most important family of enzymes at industrial level, accounting for well over 50% of the enzyme market (Feijoo-Siota and Villa, 2011). Proteases have been used industrially since the onset of enzyme technology in the first decades of the 20th century; many of the early patents issued for the use of enzymes with commercial purposes were proteases, mostly from plant (papain, bromelain) and animal (trypsin, pepsin) origin. Intended uses were in brewing and in leather and rubber manufacturing (Neidelman, 1991). In the decades that follow many large-scale industrial processes were developed using now mostly microbial proteases. A common feature of them was the degradation of proteins and most relevant areas of applications were the food and beverage (Sumantha et al., 2006), detergent (Maurer 2004), leather (Foroughi et al., 2006) and pharmaceutical sectors (Monteiro de Souza et al., 2015). Acid and neutral proteases are relevant to the food industry for the production of protein hydrolyzates (Nielsen and Olsen, 2002), beer chill-proofing (Monsan et al., 1978), meat tenderization (Ashie et al., 2002) and above all, for cheese production (Kim et al., 2004). Alkaline proteases are of paramount importance for the detergent industry (Sellami-Kamoun et al., 2008) and also in tannery (Varela et al., 1997; Thanikaivelan, 2004) and fish-meal production (Schaffeld et al., 1989; Chalamaiah et al., 2012). These conventional applications are by no means outside of continuous technological development (Monteiro de Souza et al. 2015). This is illustrated by the optimization of detergent enzyme performance under the harsh conditions of laundry at high and low temperatures, which has been a continuous challenge tackled by the construction of subtilisin (alkaline protease) variants by random and site-directed mutagenesis and by directed evolution (Kirk et al., 2002; Jares Contesini et al., 2017). It is also illustrated by the production of chymosin in microbial hosts by recombinant DNA technology and further improvement by protein engineering (Mohanty et al., 1999). Therapeutic application of proteases acting as protein hydrolases goes from conventional digestive-aids and anti-inflammatory agents to more sophisticated uses as trombolytic drugs (i.e. urokinase and tissue plasminogen activator) and more recently for the treatment of haemophilia. A comprehensive review on the therapeutic uses of proteases is suggested for the interested reader (Craik et al., 2011)The potential of hydrolytic enzymes for catalyzing reverse reactions of bond formation has been known for quite some time. However, its technological potential as catalysts for organic synthesis developed in the 1980s (Bornscheuer and Kazlauskas, 1999) paralleling the outburst of biocatalysis in non-conventional (non-aqueous) media (Illanes, 2016).Proteases can not only catalyze the cleavage of peptide bonds but, in a proper reaction medium, they can also catalyze the reaction of peptide bond formation. Proteases are highly stereo- and regiospecific, active under mild reaction conditions, do not require coenzymes and are readily available as commodity enzymes, these properties making them quite attractive catalysts for organic synthesis (Bordusa, 2002; Kumar and Bhalla, 2005). Such reactions will not proceed efficiently in aqueous medium where the hydrolytic potential of the enzyme will prevail, so reaction media at low, and hopefully controlled, water activity is necessary for peptide synthesis. This is a major threat since proteases, different from lipases, are not structurally conditioned to act in such environments. The use of proteases in peptide synthesis is analyzed in depth in section 3.4.Fil: Barberis, Sonia Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich". Universidad Nacional de San Luis; ArgentinaFil: Adaro, Mauricio Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich". Universidad Nacional de San Luis; ArgentinaFil: Origone, Anabella Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich". Universidad Nacional de San Luis; ArgentinaFil: Bersi, Grisel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich". Universidad Nacional de San Luis; ArgentinaFil: Guzman, Fanny. Pontificia Universidad Catolica de Valparaiso. Escuela de Ingeniería Bioquímica; ChileFil: Illanes, Andres. Pontificia Universidad Catolica de Valparaiso. Escuela de Ingeniería Bioquímica; Chil